Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin
Authors: Wen-Wei Liang, Rita Jui-Hsien Lu, Reyka G. Jayasinghe, Steven M. Foltz, Eduard Porta-Pardo, Yifat Geffen, Michael C. Wendl, Rossana Lazcano, Iga Kolodziejczak, Yizhe Song, Akshay Govindan, Elizabeth G. Demicco, Xiang Li, Yize Li, Sunantha Sethuraman, Samuel H. Payne, David Fenyö, Henry Rodriguez, Maciej Wiznerowicz, Hui Shen, D.R. Mani, Karin D. Rodland, Alexander J. Lazar, Ana I. Robles, Li Ding, François Aguet, Yo Akiyama, Eunkyung An, Shankara Anand, Meenakshi Anurag, Ozgun Babur, Jasmin Bavarva, Chet Birger, Michael Birrer, Anna Calinawan, Lewis C. Cantley, Song Cao, Steve Carr, Michele Ceccarelli, Daniel Chan, Arul Chinnaiyan, Hanbyul Cho, Shrabanti Chowdhury, Marcin Cieslik, Karl Clauser, Antonio Colaprico, Daniel Cui Zhou, Felipe da Veiga Leprevost, Corbin Day, Mohan Dhanasekaran, Marcin Domagalski, Yongchao Dou, Brian Druker, Nathan Edwards, Matthew Ellis, Myvizhi Esai Selvan, Alicia Francis, Gad Getz, Michael A. Gillette, Tania Gonzalez Robles, Sara Gosline, Zeynep Gümüş, David Heiman, Tara Hiltke, Runyu Hong, Galen Hostetter, Yingwei Hu, Chen Huang, Emily Huntsman, Antonio Iavarone, Eric Jaehnig, Scott Jewel, Jiayi Ji, Wen Jiang, Jared Lee Johnson, Lizabeth Katsnelson, Karen Ketchum, Karsten Krug, Chandan Kumar-Sinha, Jonathan Lei, Yuxing Liao, Caleb Lindgren, Tao Liu, Wenke Liu, Weiping Ma, Fernanda Martins Rodrigues, Wilson McKerrow, Mehdi Mesri, Alexey I. Nesvizhskii, Chelsea Newton, Robert Oldroyd, Gilbert Omenn, Amanda Paulovich, Francesca Petralia, Pietro Pugliese, Boris Reva, Kelly Ruggles, Dmitry Rykunov, Shankha Satpathy, Sara Savage, Eric Schadt, Michael Schnaubelt, Tobias Schraink, Zhiao Shi, Dick Smith, Xiaoyu Song, Vasileios Stathias, Erik Storrs, Jimin Tan, Nadezhda Terekhanova, Ratna Thangudu, Mathangi Thiagarajan, Nicole Tignor, Joshua Wang, Liang-Bo Wang, Pei Wang, Ying (Cindy) Wang, Bo Wen, Yige Wu, Lijun Yao, Tomer M. Yaron, Xinpei Yi, Bing Zhang, Hui Zhang, Qing Zhang, Xu Zhang, Zhen Zhang, Daniel W. Chan, Saravana M. Dhanasekaran, Stephan Schürer, Richard D. Smith, Matthew A. Wyczalkowski
Journal: Cancer Cell (2023)

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.